Novel signaling and treatment regimes in Anaplastic Lymphoma Kinase driven neuroblastoma models

Abstract

In this thesis we aimed to unravel the importance of Alkal2 in neuroblastoma with the aid of preclinical murine models. We tested the hypothesis that Alkal2 can potentiate murine MYCN-driven neuroblastoma in absence of activating point mutations in the anaplastic lymphoma kinase (ALK). Furthermore, we explored the effect of DNA damage response upon ALK inhibition and how ALK signaling induces its effects on DNA damage response. Here, we investigated and compared combination treatment of ALK/ATR inhibition with ATR monotherapy both in neuroblastoma cell lines and murine neuroblastoma models. We found that Alkal2 is important in tumor formation in murine MYCN driven neuroblastoma and that murine Alkal2 driven neuroblastoma is sensitive to ALK inhibition, suggesting that a subpopulation of neuroblastoma patients, such as patients with 2p gain, might benefit from ALK inhibition therapy although they lack activating point mutations in ALK. Furthermore, we underscore the potency of elimusertib/lorlatinib (ALKi/ATRi) treatment over ATR monotherapy in mouse NB models. This potency is explained in part by the impact of ALK signaling on components of the DNA damage response, together with a previously unappreciated effect of ATR inhibition in inducing differentiation. Together, our findings suggest a potentially potent treatment regime for ALK-positive high-risk neuroblastoma patients.